Synthesis of pyrazole-4-carboxamides as potential fungicide candidates

Article abstract of DOI:10.1007/s11030-020-10127-w

Abstract: A series of novel pyrazole-4-carboxamides were rationally designed, synthesized, and their structures were characterized by ¹H NMR, ¹³C NMR and HRMS. Preliminary bioassay showed that four compounds 8g, 8j, 8o and 8s exhibited more than 90% and even completed inhibition against Alternaria solani at 100?μg/mL; and 8d displayed 100% inhibition against Fusarium oxysporum at the same concentration. Moreover, 8j exhibited good in vitro fungicidal activity against A. solani with EC₅₀ value of 3.06?μg/mL, and it also displayed completed in vivo protective antifungal activity against A. solani on tomato at 10?mg/L, as boscalid did. The molecular docking results indicated that 8j exhibited the high affinity with SDH protein by H-bond and π–π stacking interactions, which may explain the reasons for its good activities. These data support that compound 8j could be used as a fungicide candidate for further study. Graphic abstract: A practical method for the synthesis of pyrazole-4-carboxamides were provided and evaluation of their antifungal activities.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s11030-020-10127-w

Molecular Diversity
https://doi.org/10.1007/s11030-020-10127-w
ORIGINAL ARTICLE
Synthesis of pyrazole‑4‑carboxamides as potential fungicide
candidates
Cuntao Dong1 · Wei Gao1 · Xiaotian Li1 · Susu Sun1 · Jingqian Huo1 · Yanen Wang1 · Da Ren1 · Jinlin Zhang1 ·
Lai Chen1
Received: 15 April 2020 / Accepted: 16 July 2020
© Springer Nature Switzerland AG 2020
Abstract
A series of novel pyrazole-4-carboxamides were rationally designed, synthesized, and their structures were characterized
by 1H NMR, 13C NMR and HRMS. Preliminary bioassay showed that four compounds 8g, 8j, 8o and 8s exhibited more
than 90% and even completed inhibition against Alternaria solani at 100 μg/mL; and 8d displayed 100% inhibition against
Fusarium oxysporum at the same concentration. Moreover, 8j exhibited good in vitro fungicidal activity against A. solani
with EC50 value of 3.06 μg/mL, and it also displayed completed in vivo protective antifungal activity against A. solani on
tomato at 10 mg/L, as boscalid did. The molecular docking results indicated that 8j exhibited the high afnity with SDH
protein by H-bond and π–π stacking interactions, which may explain the reasons for its good activities. These data support
that compound 8j could be used as a fungicide candidate for further study.
Graphic abstract
A practical method for the synthesis of pyrazole-4-carboxamides were provided and evaluation of their antifungal activities.
Keywords Synthesis · Pyrazole carboxamide · Succinate dehydrogenase inhibitor · Fungicidal activity · Molecular docking
Introduction
Cuntao Dong and Wei Gao have contributed equally to this work.
Fungicides play an important role in agricultural production
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11030-020-10127-w) contains
supplementary material, which is available to authorized users.
for controlling plant diseases [1, 2]. Succinate dehydroge-
nase inhibitors as the key class of fungicides can block the
energy synthesis of the pathogens by targeting succinate
dehydrogenase (SDH) to inhibit mitochondrial electron
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

Molecular Diversity
transfer between succinate and ubiquinone, which system is
critical for the oxygen-sensing and has been one of the most
signifcant targets for developing fungicides [3–6]. To date,
over a dozen commercial SDHIs have been launched as fun-
gicides with the characteristics of efcient, broad spectrum
activities [7].
substructures into the target molecules (Fig. 2), and homol-
ogy model and docking simulation were used to study struc-
ture–activity relationship. The target molecules with high
antifungal activities were found by the bioassay.
SDHIs are structurally very diversity but their essential
common feature consists of three parts: the amide bond, the
fve- or six-membered ring systems attached to carbonyl of
the amide bond and the amino group on the side of the amide
bond [8, 9]. Among the SDHIs, CF2H group-substituted
pyrazole carboxamides scafold were the newer represented
type (Fig. 1) [10], which are the core moiety binding to the
active site of SDH, and exhibit excellent antifungal activ-
ity. However, the amino substituent group is also impor-
tant for activity, which can be split into two main compo-
nents: the one is the liner such as a phenyl group, and the
other is the hydrophobic rest that still afects the biological
spectrum and potency of the molecules [8]. For example,
pyrazole carboxamides containing diphenylamine scafold
and biphenyl ether amine were developed, respectively, and
exhibited good antifungal activities [11–14]. Thus, making
the amino group structural diversity based on the important
CF2H group-substituted pyrazole moiety may discover novel
efcient SDHIs.
Results and discussion
Chemistry
The synthetic procedures of the target compounds 8a–8u are
described in Fig. 3. Firstly, compound 1 was produced from
the reaction between the starting materials methyl hydrazine
and ethyl 4,4-difuoro-3-oxobutanoate, then which reacted
with POCl3 in DMF to give compound 2, and compound 2
was successively oxidized, chlorinated to obtain the acid
chloride compound 4. The 2-arylbenzylamines 7 were syn-
thesized from corresponding aldehyde compound 5 by the
Suzuki cross-coupling reaction, condensation and reduc-
tion. Finally, compound 4 reacted with diferent 2-arylb-
enzylamines to give the target compounds. However, the
substrate of Ar with substituted Br group could not give the
corresponding products 6.
Crystal structure analysis
Therefore, a series of novel SDHIs were rationally
designed and synthesized based on CF2H-substituted pyra-
zole carboxamide by employing 2-arylbenzylamines as
The crystal structure of 8u was obtained by culturing a mix-
ture of ethyl acetate and dichloromethane (Fig. 4). Single
Fig. 1 CHF2 substituent pyra-
zole carboxamides of SDHIs
representative type
Fig. 2 Design strategy of the
title compounds
1 3

Molecular Diversity
Reagents and conditions: (i) POCl3, DMF; (ii) KMnO4, HCl, acetone/H2O; (iii) SOCl2, CH3CN, DMF;
(iv) ArB(OH)2, Pd(OAc)2, tricyclohexylphosphine, potassium phosphate, toluene; (v)
Cyclopropylamine, HCl, CH3OH; (vi) NaBH4, CH3OH.
Fig. 3 General synthetic route for the target compounds
by the full matrix least squares method. The fnal deviation
factors were R=0.0527 and wR=0.1385 (w=1/[σ2((Fo2)+
(0.0824P)2 + 1.1121P], where P= (Fo2 + 2F2c)/3 with (Δ/σ)
max=0.998 and S=1.045.
Antifungal activity
The in vitro antifungal activities of the target compounds
were evaluated at 100 μg/mL, and the results are listed in
Table 1 and showed that compound 8d with the olefn at
the Ar exhibited 100% growth inhibition activity against F.
oxysporum, which is slightly better than that of the posi-
Fig. 4 Crystal structure of compound 8u
tive control boscalid. Both compounds 8j and 8s displayed
100% growth inhibition against A. solani, which were simi-
crystal difraction data were collected using graphite mono-
chromatic oxidation of MoKα radiation (λ=0.71073 Å) in
the range of 1.821°≤θ≤27.879° (h, −14 to 14; k, −11 to
11; l, − 29 to 29) on the Bruker SMART 1000 CCD dif-
fractometer. A total of 5189 independent difraction data
(Rint = 0.0375) were used for structural analysis, of which
4161 observed refections with I>2σ(I).The structure was
processed using the direct method of the SHELXS-97 sys-
tem [15]. The data are improved by the full matrix least
squares method. All non-hydrogen atom coordinates were
determined by Doron Fourier synthesis. The atomic coordi-
nates and the anisotropy temperature factors were corrected
lar to that of boscalid, and 8j exhibited the higher inhibition
against F. graminearum and P. sasaki than that of boscalid
additionally.
In order to obtain the fungicidal potency of the com-
pounds with inhibition activities more than 90% at 100 μg/
mL, in vitro antifungal activity of compound 8d against
F. oxysporum, and 8g, 8j, 8o and 8s against A. solani at
50 μg/mL were further determined, respectively (Table 2).
The results showed that compound 8j remained 93%
growth inhibition against A. solani, which was a similar to
that of boscalid, and better than that of fuxapyroxad [16].
Subsequently, the median efective concentration (EC50)
1 3

Molecular Diversity
Table 1 In vitro fungicidal
activity of compounds 8a–8u
Compd. Antifungal activity (% inhibition) at 100 μg/mL
F. oa
P. a S. t A. s F. g
P. s
P. p
S. s
B. c
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
Boscalid
24 1.0 13 0.7 11 1.8
30 1.1 25 0.1 20 0.4
62 4.6 40 1.1 30 0.6 40 1.0
36 0.0 14 0.8 24 0.9 32 1.3
44 0.4 53 1.3
48 1.0 58 0.5
55 0.3 45 0.4
60 1.1 31 0.3
70 0.3 17 0.9
40 0.3 22 1.2
44 0.6 50 1.3
33 0.8 10
100 1.0 20
43 1.2 20 0.9 14
0
0
14
15
0
0
0
31
51 0.6 15 1.2 37 0.8
50 0.3 55 28 0.6
1.1 27
0
75 1.0 35 0.5 24 0.9
0
0
51
0
0
0
0
35
0
25
0
0
8
0
1.4
40
91
0
0
4
0
25 0.2 20 2.1
21 0.2 29 1.0 46
0
31 2.0 21 0.9 24 0.1
27 1.0 22 0.1 13 2.2
60 2.0 22 2.0 32 0.7 35
74 1.0 25 1.0 28 1.5 35
0
0
0
67
0
51 0.5
11 0.4 43 0.1
76 0.6 53 1.5
15 0.8 59 0.4
17 0.3 31 0.7
63
8
0
0
29 2.0 32 0.3 100
2.1 13 0.3 20 0.5 45 0.3 68 0.1 38
27 0.9 15 0.4
0
56
0
49 2.0 48
0
0
33
33
6
0
0
2.3
0
45 0.8 13
61 0.4 19
0
0
30
58 1.0 21 0.9 12 0.9
42 1.2
61
0
28 0.6
27
0
34 0.8
0
0
0
0
0
0
0
0
57 1.0 22 1.5 12
90 0.3 17 1.0 29 0.8 55
0
24 0.3
43 0.7 50 0.1
36 1.2 27 1.0
13 0.7
9
0
0
0
0
0
0
0
0
0
0
0
0
12 1.2
0 0
55 1.1
29 0.3
3
3
0
0
30
0
39
51
0
52
0
0
0
0
0
12 1.2 21
42 1.0 48
36
21
21 0.1
0.6 100
43 0.7 48 2.0 17 0.2
0.8
83 0.7 32 0.5 33 0.1 100
42
0
0
67 2.1 32
29
0
0
0
39
41
39
50 0.6 57 4.6
43 1.5 12 0.2
4
0
0
23
38
9
39 1.2 60
48 0.7 20
0
0
66 1.2 16
9
0
0
0
0
44 0.7 17 1.0
21 0.9
0.8 23
82
40 1.6 46 1.2
100 86
0
0
0
0
0
aF. o, Fusarium oxysporum; P. a, Pythium aphanidermatum; S. t, Setosphaeria turcica; A. s, Alternaria
solani; F. g, Fusarium graminearum; P. s, Pellicularia sasakii; P. p, Physalospora piricola; S. s, Sclerotinia
sclerotiorum; B. c, Botrytis cinereal
Table 3 EC50 of compound 8j against A. solani
Table 2 In vitro fungicidal activity of compounds at 50 μg/mL
Fungi
Compd.
Regression equation
R2
EC50 (μg/mL)
Compd.
Antifungal activity (% inhibition)
A. s
8j
y=−0.384+0.791x 0.982
y=−0.227+0.967x 0.916
3.06
1.72
F. o
A. s
Boscalid
8d
55 0.2
nda
nd
nd
nd
84 1.1
nd
nda
53 0.5
93 0.9
59 0.7
28 1
94 0.6
38 1.9
8g
8j
8o
Table 4 In vivo protective activity against A. solani on tomato
8s
Fungi
Compd.
Antifungal activity at
10 μg/mL (% inhibi-
tion)
Boscalid
Fluxapyroxadb
and, not determined
A. s
8j
100
100
0
0
bFluxapyroxad, the data cited from Ref. [16]
Boscalid
of compound 8j was determined (Table 3), and it exhibited
good fungicidal activity against A. solani with EC50 value
of 3.06 μg/mL, which was a similar to that of boscalid.
According to the results of in vitro antifungal activ-
ity assay, in vivo protective activity against A. solani on
tomato of compound 8j was also evaluated at 10 μg/mL. It
provided 100% protection activity as the positive control
boscalid did (Table 4).
1 3

Molecular Diversity
spectrums were obtained in deuteron chloroform (CDCl3)
and tetramethyl silane (TMS) as internal standards on a
Bruker AV-400 spectrometer operating at 400 MHz for
1H NMR and 101 MHz for 13C NMR. High-resolution
mass spectra (HRMS) were determined on a 7.0T FTICR-
MS instrument. Crystal structure was recorded by Bruker
SMART 1000 CCD difraction meter. All solvents were of
analytical grade. General procedures for the preparation of
target compounds 8a–8u.
Molecular docking
The compound 8j was docked into the active site of Gallus
gallus SDH complex to study the structure–activity rela-
tionship, and its binding afnity results showed the second
highest afnities among the 21 molecules, and its bind-
ing model was also performed by the Pymol software and
is shown in Fig. 5. The compound 8j was surrounded by
residues (e.g., Tyr58, Ile40, Trp173, Pro169, Arg43) of the
SDH protein, and H-bond was predicted between 8j and the
residue Trp173, which was a similar to that of Carboxin. In
addition, 2-chloro-phenyl group in Ar of 8j could form a π–π
stacking interaction with Tyr58, which may contribute to its
binding potency additionally. These results may explain why
8j showed good antifungal activities.
Synthesis procedure for compound 1
Forty percent methylhydrazine (28.0 mmol) in a solution
of water was added dropwise to a stirred solution of ethyl
4,4-difuoro-3-oxobutanoate (24.0 mmol) dissolved in etha-
nol (20 mL). The mixture was adjusted to pH = 5 by con-
centrated hydrochloric acid and then was heated to refux
for 4 h. After the reaction was completed, it was cooled to
room temperature and fltered. The fltrate was collected and
the solvent was evaporated to give crude product, which was
used for the next step without further purifcation.
Conclusions
In summary, a series of pyrazole-4-carboxamides com-
pounds were designed and synthesized as potential SDH
inhibitors. All target compounds structures were confrmed
by 1H NMR, 13C NMR and HRMS. The fungicidal activities
result showed that 8j exhibited the best fungicidal potency
against A. solani in vitro with EC50 value of 3.06 μg/mL and
displayed 100% protective activity against A. solani in vivo
at 10 μg/mL. The molecular docking results also explained
the reasons for its good activities. These results support that
8j could be a potential fungicidal candidate and deserved
for further studies.
Synthesis procedure for compound 2
POCl3 (50.0 mmol) was added dropwise to anhydrous N,N-
dimethylformamide (DMF) under 0–5 °C, and the mixture
was reacted for 30 min at this temperature, and then, a solu-
tion of compound 1 (17.0 mmol) in DMF was added drop-
wise. The mixture was stirred at 90–95 °C for 6 h. After the
reaction was completed, it was slowly poured into ice water,
stirred for 30 min until the solid precipitated and then fl-
tered to give yellow solid crude compound, which was used
for the next step without further purifcation.
Experimental
Synthesis procedure for compound 3
Instrumentation and materials
Compound 3 can be synthesized according to Ref. [17].
Compound 2 (70.0 mmol), acetone (1.53 mL) and H2O
(7.71 mL) were mixed, and the mixture was stirred at
YASARAY 17.6.21 software was used for molecular dock-
ing. Melting points of all compounds were determined on
an X-4 melting point apparatus and uncorrected. NMR
Fig. 5 Binding models of SDH
with 8j (a) and carboxin (b)
1 3

Molecular Diversity
60 °C for 2 min, and a solution of KMnO4 (80.0 mol) in
water (15.42 mL) was slowly added and allowed it to stir at
80–85 °C for 4.5 h. When completed, it was fltered, and the
fltrate was adjusted to pH=2 by concentrated hydrochloric
acid. The white solid was completely precipitated and fl-
tered to give compound 3, which was used for the next step
without further purifcation.
purifed column chromatography on silica gel to give com-
pounds 8a–8u in 50–73% yield.
1
The yields, physical properties and their H NMR, 13C
NMR, HRMS of the target compounds 8a–8u were shown
as below:
Data for 8a: brown solid; yield 65%; m.p.: 82–83 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.51–7.34 (m, 4H),
7.33–7.24 (m, 3H), 7.19 (d, J = 8.1 Hz, 1H), 6.72 (t,
J=54.9 Hz, 1H), 4.71 (s, 2H), 3.89 (s, 3H), 2.65 (s, 1H),
0.37 (m, 4H);13C NMR (CDCl3, 101 MHz) δ: 164.37 (s),
143.09 (t, J=27.6 Hz), 139.93 (s), 139.65 (s), 136.48 (s),
133.78 (s), 131.31 (s), 129.24 (s), 128.44 (s), 127.60 (s),
127.49 (s), 127.14 (s), 112.76 (s), 110.41 (s), 108.05 (s),
47.66 (s), 36.89 (s), 30.42 (s), 8.41 (s); HRMS calcd for
C22H19Cl2F2N3O (M+H)+: 450.0873, found 450.0947.
Synthesis procedure for compound 4
Sulfoxide (14.0 mmol) was added to a solution of compound
3 (1.4 mmol) in acetonitrile under ice bath, and a catalytic
amount of DMF (0.1 mmol) was also added, and then, it was
refuxed for 2 h. When completed, the solvent was evapo-
rated to give compound 4, which was used for the next step
without further purifcation.
Synthesis procedure for compounds 6a–6u
Data for 8b: yellow solid; yield 68%; m.p.: 114–116 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.45 (s, 1H), 7.29–7.15
(m, 6H), 6.71 (t, J=54.9 Hz, 1H), 4.70 (s, 2H), 3.88 (s,
3H), 2.65 (s, 1H), 2.40 (s, 3H), 0.36 (m, 4H); 13C NMR
(CDCl3, 101 MHz) δ: 164.37 (s), 143.21 (t, J=27.6 Hz),
139.92 (s), 137.35 (s), 136.68 (s), 136.53 (s), 133.56 (s),
131.36 (s), 129.13 (s), 127.36 (s), 127.07 (s), 115.13
(s), 112.77 (s), 110.41 (s), 108.06 (s), 47.67 (s), 36.89
(s), 30.40 (s), 21.21 (s), 8.36 (s); HRMS calcd for
C23H21Cl2F2N3O (M+H)+: 464.1030, found: 464.1102.
Compound 5 (4.0 mmol), Ar-boronic acid (6.0 mmol),
palladium acetate (0.4 mmol), tricyclohexylphosphine
(0.8 mmol), potassium phosphate (11.8 mmol, 2.5 g) and
H2O (5 mL) were added to toluene (20 mL). The reaction
mixture was stirred at 110 °C overnight under nitrogen.
When completed, it was poured into water (50 mL) and
extracted with ethyl acetate (20 mL×3). The organic layer
was collected and dried over anhydrous sodium sulfate and
fltered. The solvent was evaporated to give compounds
6a–6u, which were used for the next step without further
purifcation.
1
Data for 8c: yellow oil; yield 59%; H NMR (CDCl3,
400 MHz) δ: 7.72 (s, 1H), 7.58 (t, J=8.5 Hz, 2H), 7.48 (s,
1H), 7.32 (s, 2H), 7.26–7.18 (m, 1H), 6.75 (t, J=54.2 Hz,
1H), 4.80 (d, J=43.6 Hz, 2H), 3.91 (d, J=7.5 Hz, 3H),
2.71 (s, 1H), 2.07 (s, 2H), 1.61 (s, 1H), 1.28 (t, J=6.3 Hz,
3H), 0.39 (m, 4H); 13C NMR (CDCl3, 101 MHz) δ:
164.35 (s), 142.77 (t, J=27.6 Hz), 139.94 (s), 137.87 (s),
136.53 (s), 134.86 (s), 133.54 (s), 131.36 (s), 130.59 (s),
129.17 (s), 127.90 (s), 126.95 (s), 112.76 (s), 110.40 (s),
108.04 (s), 47.67 (s), 36.86 (s), 30.41 (s), 28.56 (s), 15.51
(s), 8.38 (s); HRMS calcd for C24H23Cl2F2N3O (M+H)+:
478.1186, found: 478.1257.
Synthesis procedure for compounds 7a–7u
Cyclopropylamine (0.78 mol) was added to a solution of
compounds 6 (0.65 mol) in methanol (15 mL) and stirred
about 1–2 h, and then, sodium borohydride (2.26 mol) was
solely added. It was allowed to react at room temperature for
2 h. When completed, the mixture was washed with 30 mL
of saturated brine and then was extracted with ethyl acetate.
The solvent was evaporated and compounds 7a–7u were
obtained. They can be used for the next step without further
purifcation.
1
Data for 8d: yellow oil; yield 63%; H NMR (CDCl3,
400 MHz) δ: 7.48 (d, J=7.1 Hz, 3H), 7.24 (dt, J=17.4,
16.6 Hz, 4H), 6.75 (dt, J =66.8, 40.4 Hz, 1H), 5.81 (d,
J = 17.6 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 4.72 (s,
2H), 3.88 (s, 3H), 2.66 (s, 1H), 0.37 (m, 4H); 13C NMR
(CDCl3, 101 MHz) δ: 164.38 (s), 143.08 (t, J=27.6 Hz),
139.55 (s), 139.08 (s), 136.91 (s), 136.55 (s), 136.24 (s),
133.85 (s), 131.23 (s), 129.48 (s), 127.49 (s), 127.18 (s),
126.26 (s), 114.49 (s), 112.78 (s), 110.42 (s), 108.06 (s),
47.68 (s), 36.89 (s), 30.45 (s), 8.43 (s); HRMS calcd for
C24H21Cl2F2N3O (M+H)+: 476.1030, found: 476.1101.
Synthesis procedure for compounds 8a‑8u
Triethylamine (1.38 mol) was added to a solution of com-
pounds 7 (1.15 mol) in anhydrous dichloromethane (10 mL),
and then, a solution of compound 4 (1.38 mol) in anhydrous
dichloromethane was slowly added under 0–5 °C. The reac-
tion was stirred at room temperature for 2 h. When com-
pleted, the reaction mixture was washed with saturated brine
(30 mL×3) and dried by anhydrous sodium sulfate. After
fltration, the solvent was evaporated. The residue was then
1 3

Molecular Diversity
Data for 8e: brown crystal; yield 73%; m.p.: 125–
(t, J=54.6 Hz, 1H), 4.67 (s, 2H), 3.89 (s, 3H), 2.68 (s,
1H), 0.39 (m, 4H); 13C NMR(CDCl3, 101 MHz) δ: 164.34
(s), 163.55 (s), 161.09 (s), 143.07 (t, J=27.7 Hz), 138.80
(s), 136.61 (s), 135.58 (s), 133.98 (s), 131.37 (s), 130.90
(s), 130.82 (s), 127.50 (s), 127.20 (s), 115.53 (s), 115.32
(s), 112.79 (s), 110.43 (s), 47.70 (s), 36.89 (s), 30.48 (s),
8.43 (s); HRMS calcd for C22H18Cl2F3N3O (M + H)+:
468.0799, found: 468.0853.
1
127 °C; H NMR (400 MHz, CDCl3) δ: 7.46 (s, 1H),
7.32–7.25 (m, 3H), 7.20 (dd, J=13.8, 8.0 Hz, 3H), 6.73
(t, J=54.9 Hz, 1H), 4.72 (s, 2H), 3.89 (s, 5H), 2.97 (dt,
J=13.8, 6.8 Hz, 1H), 2.66 (s, 1H), 1.30 (d, J=6.9 Hz,
6H), 0.37 (m, 4H); 13C NMR(CDCl3, 101 MHz) δ: 164.35
(s), 148.25 (s), 143.08 (t, J=27.6 Hz), 139.95 (s), 137.01
(s), 136.56 (s), 133.54 (s), 131.38 (s), 129.16 (s), 127.37
(s), 127.06 (s), 126.48 (s), 112.76 (s), 110.41 (s), 108.05
(s), 47.71 (s), 36.87 (s), 33.85 (s), 30.43 (s), 23.99 (s),
8.40 (s); HRMS calcd for C25H25Cl2F2N3O (M + H)+:
492.1343, found: 492.1414.
1
Data for 8j: brown oil; yield 66%; H NMR (CDCl3,
400 MHz) δ: 7.48 (s, 2H), 7.39–7.28 (m, 3H), 7.27 (s,
1H), 7.13 (d, J=7.5 Hz, 1H), 6.72 (t, J=54.4 Hz, 1H),
4.53 (s, 2H), 3.90 (s, 3H), 2.73 (s, 1H), 0.62 (s, 1H), 0.42
(m, 4H); 13C NMR (CDCl3, 101 MHz) δ: 164.42 (s),
142.96 (t, J = 27.8 Hz), 138.17 (s), 137.33 (s), 136.81
(s), 134.45 (s), 133.87 (s), 133.45 (s), 131.37 (s), 131.21
(s), 129.67 (s), 129.43 (s), 127.20 (s), 127.13 (s), 112.76
(s), 110.41 (s), 108.05 (s), 47.69 (s), 36.90 (s), 30.51 (s),
8.65 (s); HRMS calcd for C22H18Cl3F2N3O (M + H)+:
484.0484, found: 484.0559.
Data for 8f: yellow solid; yield 74%; m.p.: 106–108 °C;
1H NMR (CDCl3, 400 MHz)δ: 7.44 (d, J=8.1 Hz, 3H),
7.29–7.13 (m, 4H), 6.71 (t, J=54.8 Hz, 1H), 4.72 (s, 2H),
3.88 (s, 3H), 2.66 (s, 1H), 1.36 (s, 9H), 0.36 (m, 4H);
13C NMR(CDCl3, 101 MHz) δ: 164.36 (s), 143.08 (t,
J = 27.6 Hz), 139.88 (s), 136.56 (s), 133.53 (s), 131.40
(s), 128.91 (s), 127.33 (s), 125.33 (s), 112.76 (s), 112.08
(s), 110.41 (s), 109.73 (s), 108.05 (s), 107.37 (s), 47.73
(s), 36.89 (s), 34.62 (s), 31.37 (s), 30.45 (s), 8.42 (s);
HRMS calcd for C26H27Cl2F2N3O (M+H)+: 506.1499,
found: 506.1568.
1
Data for 8k: brown oil; yield 77%; H NMR (CDCl3,
400 MHz) δ: 7.48 (s, 1H), 7.37 (d, J=4.1 Hz, 2H), 7.32–
7.27 (m, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.72 (t, J=54.8 Hz,
1H), 4.68 (s, 2H), 3.89 (s, 3H), 2.67 (s, 1H), 0.40 (m,
4H); 13C NMR (CDCl3, 101 MHz) δ: 164.35 (s), 143.11
(t, J=27.7 Hz), 141.43 (s), 138.40 (s), 136.51 (s), 134.34
(s), 131.16 (s), 129.74 (s), 129.27 (s), 127.79 (s), 127.68
(s), 127.49 (s), 127.30 (s), 114.98 (s), 112.77 (s), 110.41
(s), 108.06 (s), 47.69 (s), 36.91 (s), 30.47 (s), 8.52 (s);
HRMS calcd for C22H18Cl3F2N3O (M+H)+: 484.0484,
found: 484.0556.
Data for 8g: brown solid; yield 43%; m.p.: 53–54 °C;
1H NMR (CDCl3, 400 MHz)δ: 7.49 (s, 1H), 7.38 (d,
J=5.4 Hz, 1H), 7.30 (dd, J=8.1, 1.7 Hz, 1H), 7.27–7.08
(m, 4H), 6.71 (t, J = 54.7 Hz, 1H), 4.61 (s, 2H), 3.87
(s, 3H), 2.66 (s, 1H), 0.38 (m, 4H); 13C NMR(CDCl3,
101 MHz)δ: 164.34 (s), 160.68 (s), 158.24 (s), 143.07
(t, J = 27.5 Hz), 137.67 (s), 134.54 (s), 133.32 (s),
131.68 (s), 130.03 (s), 129.95 (s), 127.56 (s), 127.26 (s),
124.35 (s), 115.65 (s), 112.75 (s), 110.40 (s), 108.04 (s),
47.57 (s), 36.87 (s), 30.42 (s), 8.40 (s); HRMS calcd for
C22H18Cl2F3N3O (M+H)+: 468.0799, found: 468.0854.
Data for 8l: brown solid; yield 67%; m.p.: 113–114 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.51–7.37 (m, 3H),
7.29 (dd, J=8.2, 1.9 Hz, 2H), 7.25–7.20 (m, 1H), 7.15
(d, J = 8.1 Hz, 1H), 6.72 (t, J = 54.6 Hz, 1H), 4.67 (s,
2H), 3.89 (s, 3H), 2.68 (s, 1H), 0.40 (m, 4H); 13C NMR
(CDCl3, 101 MHz) δ: 164.34 (s), 143.04 (t, J=27.7 Hz),
138.55 (s), 138.04 (s), 136.51 (s), 134.16 (s), 133.75 (s),
131.19 (s), 130.55 (s), 128.66 (s), 127.51 (s), 127.25 (s),
126.31 (s), 114.95 (s), 112.77 (s), 110.41 (s), 108.06 (s),
47.70 (s), 36.89 (s), 30.49 (s), 8.45 (s); HRMS calcd for
C22H18Cl3F2N3O (M+H)+: 484.0484, found: 484.0555.
1
Data for 8h: brown oil; yield 58%; H NMR (CDCl3,
400 MHz) δ: 7.48 (s, 1H), 7.45–7.36 (m, 1H), 7.30 (d,
J=8.2 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.09 (dd, J=8.0,
6.1 Hz, 2H), 7.02 (d, J=7.6 Hz, 1H), 6.73 (t, J=55.2 Hz,
1H), 4.69 (s, 2H), 3.90 (s, 3H), 2.68 (s, 1H), 0.40 (m, 4H);
13C NMR (CDCl3, 101 MHz) δ: 164.36 (s), 163.82 (s),
161.36 (s), 142.77 (t, J = 77.2 Hz), 138.56 (s), 136.50
(s), 134.28 (s), 131.13 (s), 130.08 (s), 129.99 (s), 127.61
(s), 127.27 (s), 125.10 (s), 114.68 (s), 112.77 (s), 110.42
(s), 108.06 (s), 47.66 (s), 36.89 (s), 30.48 (s), 8.48 (s);
HRMS calcd for C22H18Cl2F3N3O (M+H)+: 468.0799,
found: 468.0851.
1
Data for 8m: yellow oil; yield 55%; H NMR (CDCl3,
400 MHz) δ: 7.49 (d, J=22.4 Hz, 2H), 7.32 (t, J=7.9 Hz,
2H), 7.21 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H),
6.72 (t, J=54.7 Hz, 1H), 4.51 (s, 2H), 3.90 (s, 3H), 2.75
(s, 1H), 0.44 (m, 4H); 13C NMR (CDCl3, 101 MHz) δ:
164.36 (s), 143.06 (t, J = 27.7 Hz), 137.45 (s), 136.74
(s), 135.60 (s), 134.81 (s), 134.65 (s), 134.29 (s), 133.84
(s), 132.11 (s), 131.14 (s), 129.50 (s), 128.90 (s), 127.29
Data for 8i: brown solid; yield 63%; m.p.: 100–102 °C;
1H NMR (CDCl3, 400 MHz)δ: 7.46 (s, 1H), 7.27 (dd,
J=6.9, 5.1 Hz, 3H), 7.14 (dd, J=16.7, 8.3 Hz, 3H), 6.72
1 3

Molecular Diversity
(s), 112.79 (s), 110.43 (s), 108.08 (s), 47.74 (s), 36.89
(s), 30.59 (s), 8.59 (s); HRMS calcd for C22H17Cl4F2N3O
(M+H)+: 518.0094, found: 518.0163.
47.66 (s), 36.88 (s), 30.41 (s), 8.38 (s); HRMS calcd for
C23H21Cl2F2N3O2 (M+H)+: 480.0979, found: 480.1046.
Data for 8r: brown solid; yield 71%; m.p.: 69–70 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.55 (d, J = 10.1 Hz,
2H), 7.40 (s, 1H), 7.28 (dd, J=8.5, 2.0 Hz, 1H), 6.75 (t,
J=54.4 Hz, 1H), 6.51 (s, 2H), 4.96 (s, 2H), 3.91 (s, 3H),
2.77 (s, 1H), 0.53 (m, 4H); 13C NMR(CDCl3, 101 MHz)
δ: 164.54 (s), 142.60 (t, J=27.8 Hz), 138.77 (s), 135.60
(s), 134.04 (s), 129.45 (s), 128.08 (s), 127.67 (s), 127.39
(s), 126.45 (s), 114.91 (s), 112.76 (s), 111.57 (s), 110.40
(s), 109.36 (s), 48.69 (s), 36.89 (s), 30.79 (s), 8.51 (s);
HRMS calcd for C20H17Cl2F2N3O2 (M+H)+: 440.0666,
found: 440.0738.
1
Data for 8n: yellow oil; yield 71%; H NMR (CDCl3,
400 MHz) δ: 7.88 (s, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.71
(d, J=11.3 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.62 (s,
1H), 7.36 (d, J=7.9 Hz, 1H), 6.71 (t, J=54.6 Hz, 1H),
4.78 (s, 2H), 3.88 (s, 3H), 2.72 (s, 1H), 0.41 (m, 4H);
13C NMR (CDCl3, 101 MHz) δ: 164.51 (s), 143.07 (t,
J = 27.8 Hz), 141.17 (s), 139.63 (s), 135.47 (s), 132.73
(s), 131.21 (q, J=25.1 Hz), 130.76 (s), 130.53 (s), 129.32
(s), 128.99 (s), 126.29 (s), 125.95 (s), 124.35 (s), 123.94
(s), 122.83 (s), 112.90 (s), 110.55 (s), 47.97 (s), 36.87
(s), 30.66 (s), 8.43 (s); HRMS calcd for C23H18Cl2F5N3O
(M+H)+: 518.0747, found: 518.0828.
1
Data for 8s: yellow oil; yield 73%; H NMR (CDCl3,
400 MHz) δ: 7.46 (s, 1H), 7.39 (d, J=4.3 Hz, 1H), 7.33
(d, J=8.1 Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.15–7.09
(m, 1H), 7.03 (s, 1H), 6.74 (t, J=55.0 Hz, 1H), 4.86 (s,
2H), 3.90 (s, 3H), 2.71 (s, 1H), 0.44 (m, 4H); 13C NMR
(CDCl3, 101 MHz) δ: 165.12 (s), 146.34 (t, J=27.8 Hz),
140.20 (s), 137.84 (s), 134.42 (s), 132.51 (s), 132.07 (s),
131.42 (s), 127.94 (s), 127.51 (s), 127.35 (s), 126.03 (s),
112.49 (s), 110.14 (s), 107.79 (s), 48.65 (s), 36.91 (s),
31.14 (s), 10.11 (s); HRMS calcd for C20H17Cl2F2N3OS
(M+H)+: 456.0437, found: 456.0509.
Data for 8o: brown solid; yield 95%; m.p.: 129–131 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.46 (s, 1H), 7.42–7.35
(m, 1H), 7.28 (dd, J=8.2, 1.9 Hz, 1H), 7.14 (d, J=7.8 Hz,
2H), 7.03 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H),
6.72 (t, J=54.7 Hz, 1H), 4.88 (s, 1H), 4.23 (s, 1H), 3.89
(s, 3H), 3.79 (s, 3H), 2.63 (s, 1H), 0.36 (d, J=23.6 Hz,
4H); 13C NMR (CDCl3, 101 MHz) δ: 164.39 (s), 156.51
(s), 143.21 (t, J=27.5 Hz), 137.86 (s), 136.32 (s), 133.69
(s), 131.57 (s), 131.07 (s), 129.50 (s), 128.39 (s), 127.06
(s), 120.74 (s), 112.76 (s), 110.64 (s), 110.41 (s), 108.05
(s), 99.99 (s), 55.41 (s), 47.46 (s), 36.88 (s), 30.31 (s),
8.68 (s); HRMS calcd for C23H21Cl2F2N3O2 (M + H)+:
480.0979, found: 480.1050.
1
Data for 8t: brown oil; yield 68%; H NMR (CDCl3,
400 MHz) δ: 7.91 (dd, J = 7.8, 4.6 Hz, 2H), 7.62–7.36
(m, 7H), 7.25 (t, J = 6.3 Hz, 1H), 6.71 (t, J = 54.8 Hz,
1H), 4.44 (d, J=34.6 Hz, 2H), 3.87 (s, 3H), 2.65 (s, 1H),
0.28 (m, 4H); 13C NMR (CDCl3, 101 MHz) δ: 164.39
(s), 143.06 (t, J=27.5 Hz), 137.97 (s), 137.76 (s), 137.10
(s), 134.17 (s), 133.55 (s), 131.96 (s), 128.44 (s), 128.33
(s), 127.14 (s), 126.58 (s), 125.62 (s), 125.33 (s), 112.78
(s), 110.42 (s), 108.06 (s), 47.85 (s), 36.88 (s), 30.42 (s),
8.40 (s); HRMS calcd for C26H21Cl2F2N3O (M + H)+:
500.1030, found: 500.1099.
Data for 8p: brown solid; yield 60%; m.p.: 94–95 °C;
1H NMR (CDCl3, 400 MHz)δ: 7.46 (s, 1H), 7.35 (t,
J=7.8 Hz, 1H), 7.31–7.27 (m, 1H), 7.19 (d, J=8.2 Hz,
1H), 6.96–6.86 (m, 2H), 6.86–6.57 (m, 2H), 4.71 (s, 2H),
3.90 (s, 2H), 3.84 (s, 3H), 2.67 (s, 1H), 0.39 (m, 4H); 13
C
NMR(CDCl3, 101 MHz) δ: 164.45 (s), 159.50 (s), 143.21
(t, J=27.5 Hz), 141.02 (s), 139.75 (s), 136.48 (s), 133.83
(s), 131.16 (s), 129.48 (s), 127.40 (s), 127.09 (s), 126.37
(s), 121.65 (s), 115.04 (s), 112.93 (s), 110.41 (s), 108.05
(s), 55.32 (s), 47.71 (s), 36.89 (s), 30.48 (s), 8.42 (s);
HRMS calcd for C23H21Cl2F2N3O2 (M+H)+: 480.0979,
found: 480.1051.
Data for 8u: yellow crystal; yield 70%; m.p.: 157–158 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.71 (d, J=8.0 Hz, 1H),
7.63 (d, J=7.5 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.48 (s,
1H), 7.34 (dd, J=13.7, 5.1 Hz, 2H), 7.28 (d, J=7.7 Hz,
1H), 6.96–6.58 (m, 2H), 5.07 (s, 2H), 3.90 (s, 3H), 2.79
(d, J=4.3 Hz, 1H), 0.51 (d, J=12.5 Hz, 4H); 13C NMR
(CDCl3, 101 MHz) δ: 164.49 (s), 154.77 (s), 153.94 (s),
143.19 (t, J = 27.5 Hz), 136.88 (s), 135.23 (s), 130.37
(s), 128.71 (s), 127.79 (s), 127.53 (s), 124.81 (s), 123.20
(s), 121.18 (s), 115.02 (s), 112.85 (s), 111.28 (s), 110.50
(s), 108.14 (s), 106.06 (s), 48.76 (s), 36.91 (s), 30.84 (s),
8.54 (s); HRMS calcd for C24H19Cl2F2N3O2 (M + H)+:
490.0822, found: 490.0893.
Data for 8q: brown solid; yield 68%; m.p.: 127–128 °C;
1H NMR (CDCl3, 400 MHz) δ: 7.45 (s, 1H), 7.28 (d,
J=2.1 Hz, 1H), 7.20 (dd, J=19.9, 8.0 Hz, 3H), 6.97 (d,
J=8.3 Hz, 2H), 6.72 (t, J=55.0 Hz, 1H), 4.71 (s, 2H),
3.89 (s, 3H), 3.86 (s, 3H), 2.66 (s, 1H), 0.37 (m, 4H);
13C NMR (CDCl3, 101 MHz) δ: 164.35 (s), 159.11 (s),
143.07 (t, J=27.8 Hz), 139.60 (s), 136.61 (s), 133.46 (s),
131.92 (s), 131.45 (s), 130.36 (s), 127.38 (s), 127.07 (s),
113.85 (s), 112.77 (s), 110.41 (s), 108.06 (s), 55.35 (s),
1 3

Molecular Diversity
evaluation of isothiazole based 1,2,4-trizaole derivatives. Chin J
Chem 36(8):731–736. https://doi.org/10.1002/cjoc.201700765
3. Bardas GA, Veloukas T, Koutita O, Karaoglanidis GS (2010) Multi-
ple resistance of Botrytis cinerea from kiwi fruit to SDHIs, QoIs and
fungicides of other chemical groups. Pest Manag Sci 66(9):967–973.
https://doi.org/10.1002/ps.1968
Determination of antifungal activity
In vitro antifungal activity
In vitro antifungal activities against Fusarium oxysporum,
Pythium aphanidermatum, Setosphaeria turcica, Alter-
naria solani, Fusarium graminearum, Pellicularia sasakii,
Physalospora piricola, Sclerotinia sclerotiorum and Botrytis
cinereal of all compounds were determined according to
an established method [18]. The inhibition activities of any
target compounds showed that more than 90% at 100 μg/
mL were further evaluated at 50 μg/mL, and the median
efective concentration (EC50) of 8j was determined by a
reported method [19].
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of gray mold by the novel SDHI fungicide benzovindifupyr com-
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jafc.8b01936
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In vivo fungicidal activity
7. Gutierrez-Alonso O, Hawkins NJ, Cools HJ, Shaw MW, Fraaije
BA (2017) Dose-dependent selection drives lineage replacement
during the experimental evolution of SDHI fungicide resistance
in Zymoseptoria tritici. Evol Appl 10(10):1055–1066. https://doi.
org/10.1111/eva.12511
The in vivo fungicidal activity of 8j against A. solani on
tomato leaves was evaluated according to the following
procedures [20]. The target compound solution (10 μg/
mL) was sprayed onto the tomato plants. The control plants
were sprayed with water. After 24 h, the tomato plants were
infected with spore suspension of the A. solani (concentra-
tion: 1×105 spore/mL) and then cultured in the greenhouse.
The disease percentage of diseased control plants was com-
pared with the healthy control plants by considering the dis-
ease control is set as 100 and no disease as 0. Boscalid was
used as a positive control.
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covery of novel chiral antifungal amides with 2-(2-oxazolinyl)aniline
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8965. https://doi.org/10.1021/acs.jafc.8b02778
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Kalinina TA, Glukhareva TV (2019) Synthesis and biological activ-
ity of novel succinate dehydrogenase inhibitor derivatives as potent
fungicide candidates. J Agric Food Chem 67(47):13185–13194.
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Molecular docking
11. Xiong L, Li H, Jiang L-N, Ge J-M, Yang W-C, Zhu XL, Yang G-F
(2017) Structure-Based Discovery of Potential Fungicides as Suc-
cinate Ubiquinone Oxidoreductase Inhibitors. J Agric Food Chem
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synthesis, and antifungal activities of novel aromatic carboxa-
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p.2019.05.007
The molecular structure 8j was drawn by ChemDraw Ultra
14.0 and then saved as mol2 fle. The crystal structure of
SDH of Gallus gallus (PDB: 2FBW) was obtained from the
PDB database (https://www.rcsb.org/structure/2fbw) [21],
which was applied as the target for molecular docking by
YASARA software. The docking models were analyzed by
the AutoDock Vina program. Pymol software was used to
show the docking models.
14. Lv X-H, Ren Z-L, Liu P, Li B-X, Li Q-S, Chu M-J, Cao H-Q (2017)
Design, synthesis and biological evaluation of novel nicotinamide
derivatives bearing a substituted pyrazole moiety as potential
SDH inhibitors. Pest Manage Sci 73(8):1585–1592. https://doi.
org/10.1002/ps.4488
Acknowledgements This work was supported in part by the National
Natural Science Foundation of China (No. 31871981); Youth Natu-
ral Science Foundation of Hebei Province (No. B2019204030); and
the starting Scientifc Research Foundation for the introduced talents
of Hebei Agricultural University (No. 201842); Modern Agriculture
Industry Technology System Innovation Team of Phase II of Hebei
Province (No. HB2018020205).
15. Altomare A, Burla MC, Camalli M, Cascarano GL, Giacovazzo C,
Guagliardi A, Moliterni AGG, Polidori G, Spagna R (1999) SIR97:
a new tool for crystal structure determination and refnement. J Appl
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Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
Afliations
Cuntao Dong1 · Wei Gao1 · Xiaotian Li1 · Susu Sun1 · Jingqian Huo1 · Yanen Wang1 · Da Ren1 · Jinlin Zhang1 ·
Lai Chen1
1
* Jinlin Zhang
zhangjinlin@hebau.edu.cn
College of Plant Protection, Hebei Agricultural University,
Baoding 071001, People’s Republic of China
* Lai Chen
chenlai@hebau.edu.cn
1 3